Cyanide constitutes a major chemical threat to civilians and military personnel with numerous sources of potential cyanide exposure, including fires and terrorist attacks. In severe cyanide poisonings, rapid intervention is the key, and treatments require a "three minute solution", akin to the nerve agent antidote kit. Currently there are no antidote options that meet these criteria. We (Nagasawa et al) have recently developed a series of prototype cyanide antidotes that detoxify cyanide by converting cyanide to the non-toxic thiocyanate. We have also developed a unique mouse model-that minimizes the numbers of animals required-for assessing the toxicity of sub-lethal doses of cyanide, which is highly amenable for evaluating the antidotal efficacy of our compounds. One antidote of the above is highly water soluble, rapid acting, does not require IV infusion and has been selected as a prime candidate for further preclinical development. In addition, we (Boss and colleagues) have shown that cobinamide, the penultimate precursor in the biosynthesis of cobalamin, is highly effective in protecting mice from cyanide. This antidote works, thorough sequestration of cyanide and excretion of the resulting complex in urine, a different mechanism than the above antidotes. Cobinamide is highly water soluble, rapid acting and does not require IV infusion. We (Brenner et al.) have also developed a reliable, reproducible rabbit model of cyanide toxicity and demonstrated the ability of diffuse optical spectroscopy (DOS) technologies developed at Beckman Laser Institute to noninvasively assess the pathophysiologic events occurring during cyanide toxicity and reversal with standard antidotes. This use of novel, validated non-invasive optical technologies for quantitative measurement of a range of physiologic endpoints of cyanide toxicity and treatment response, should allow accelerated development and refinement of testing of the drug candidates developed by the Boss and Nagasawa/Patterson labs. Having already established "proof of concept" that our antidotes protect against cyanide toxicity in mice, we will a) simultaneously evaluate the efficacy of the compounds individually and in combination in the Brenner rabbit model and the Nagasawa/Patterson mouse model and piglet model b) accelerate preclinical toxicity, ADME studies etc. for these compounds individually and in combination c) file an IND to the FDA and d) initiate Phase I and limited Phase 2 clinical trials. We anticipate that these combinations will be more effective than the single drugs. If this is found to be the case, such a combination (cocktail) may become the standard for protection against cyanide exposure by the military as well as by first responders.